Genome-wide association study identifies susceptibility loci for IgA nephropathy

We carried out a genome-wide association study of IgA nephropathy, a major cause of kidney failure worldwide. We studied 1,194 cases and 902 controls of Chinese Han ancestry, with targeted follow up in Chinese and European cohorts comprising 1,950 cases and 1,920 controls. We identified three independent loci in the major histocompatibility complex, as well as a common deletion of CFHR1 and CFHR3 at chromosome 1q32 and a locus at chromosome 22q12 that each surpassed genome-wide significance (P values for association between 1.59 × 10?2? and 4.84 × 10?? and minor allele odds ratios of 0.63-0.80). These five loci explain 4-7% of the disease variance and up to a tenfold variation in interindividual risk. Many of the alleles that protect against IgA nephropathy impart increased risk for other autoimmune or infectious diseases, and IgA nephropathy risk allele frequencies closely parallel the variation in disease prevalence among Asian, European and African populations, suggesting complex selective pressures.     

Stopping RNA interference at the seed

MicroRNAs (miRNAs) regulate expression of more than one half of the genes in the human genome. A study now reports a new method for selectively silencing whole families of miRNAs, thus providing a new paradigm for disease therapy.     

SLX4, a coordinator of structure-specific endonucleases, is mutated in a new Fanconi anemia subtype

DNA interstrand crosslink repair requires several classes of proteins, including structure-specific endonucleases and Fanconi anemia proteins. SLX4, which coordinates three separate endonucleases, was recently recognized as an important regulator of DNA repair. Here we report the first human individuals found to have biallelic mutations in SLX4. These individuals, who were previously diagnosed as having Fanconi anemia, add SLX4 as an essential component to the FA-BRCA genome maintenance pathway.     

Neural mechanisms of operant conditioning and learning-induced behavioral plasticity in <Emphasis Type="Italic">Aplysia</Emphasis>

Associative learning in goal-directed behaviors, in contrast to reflexive behaviors, can alter processes of decision-making in the selection of appropriate action and its initiation, thereby enabling animals, including humans, to gain a predictive understanding of their external environment. In the mollusc Aplysia, recent studies on appetitive operant conditioning in which the animal learns about the positive consequences of its behavior have provided insights into this form of associative learning which, although ubiquitous, remains mechanistically poorly understood. The findings support increasing evidence that central circuit- and cell-wide sites other than chemical synaptic connections, including electrical coupling and membrane conductances controlling intrinsic neuronal excitability and underlying voltage-dependent plateauing or oscillatory mechanisms, may serve as the neural substrates for behavioral plasticity resulting from operant conditioning. Aplysia therefore continues to provide a model system for understanding learning and memory formation that enables establishing the neurobiological links between behavioral, network, and cellular levels of analysis.     

Effects of livestock grazing exlosure on aquatic macroinvertebrates in a montane stream, New Mexico

Aquatic macroinvertebrate populations inhabiting reaches of a stream within areas excluded from livestock grazing for a decade were markedly different from those in grazed areas when density, biomass, biotic condition indices, and mean chi square indices of the two populations were compared. Increased densities and biomasses of more tolerant forms of macroinvertebrates were observed in grazed reaches. Because pretreatment data were not available, differences in macroinvertebrate populations and relative tolerances of taxa in grazed and ungrazed areas could be as easily attributed to linear changes in stream habitat as to removal of domestic livestock. Results of this study have implications for the design of future research on the effects of livestock grazing on stream environments and biota: (1) baseline/pretreatment information is prerequisite, and (2) the study should take a watershed (ecosystem) approach.     

Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus

Aicardi-Goutières syndrome (AGS) presents as a severe neurological brain disease and is a genetic mimic of the sequelae of transplacentally acquired viral infection. Evidence exists for a perturbation of innate immunity as a primary pathogenic event in the disease phenotype. Here, we show that TREX1, encoding the major mammalian 3' --> 5' DNA exonuclease, is the AGS1 gene, and AGS-causing mutations result in abrogation of TREX1 enzyme activity. Similar loss of function in the Trex1(-/-) mouse leads to an inflammatory phenotype. Our findings suggest an unanticipated role for TREX1 in processing or clearing anomalous DNA structures, failure of which results in the triggering of an abnormal innate immune response.     

Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6

Urolithiasis is one of the most common urologic diseases in industrialized societies. Calcium oxalate is the predominant component in 70-80% of kidney stones, and small changes in urinary oxalate concentration affect the risk of stone formation. SLC26A6 is an anion exchanger expressed on the apical membrane in many epithelial tissues, including kidney and intestine. Among its transport activities, SLC26A6 mediates Cl(-)-oxalate exchange. Here we show that mutant mice lacking Slc26a6 develop a high incidence of calcium oxalate urolithiasis. Slc26a6-null mice have significant hyperoxaluria and elevation in plasma oxalate concentration that is greatly attenuated by dietary oxalate restriction. In vitro flux studies indicated that mice lacking Slc26a6 have a defect in intestinal oxalate secretion resulting in enhanced net absorption of oxalate. We conclude that the anion exchanger SLC26A6 has a major constitutive role in limiting net intestinal absorption of oxalate, thereby preventing hyperoxaluria and calcium oxalate urolithiasis.     

A unified mixed-model method for association mapping that accounts for multiple levels of relatedness

As population structure can result in spurious associations, it has constrained the use of association studies in human and plant genetics. Association mapping, however, holds great promise if true signals of functional association can be separated from the vast number of false signals generated by population structure. We have developed a unified mixed-model approach to account for multiple levels of relatedness simultaneously as detected by random genetic markers. We applied this new approach to two samples: a family-based sample of 14 human families, for quantitative gene expression dissection, and a sample of 277 diverse maize inbred lines with complex familial relationships and population structure, for quantitative trait dissection. Our method demonstrates improved control of both type I and type II error rates over other methods. As this new method crosses the boundary between family-based and structured association samples, it provides a powerful complement to currently available methods for association mapping.